Background: Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. Objective: We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms. Materials and Methods: Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very longchain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation. Results: Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP. Conclusion: These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.

Proton transfer (PT) in organic crystals creates localized charges and strong hydrogen bonding (HB), making the self-consistent field (SCF) calculation of core-ionized and core-excited states challenging. Today most corresponding X-ray spectral measurements are interpreted based on empirical fitting and/or chemical intuitions. Here we present a systematic quantum mechanical/molecular mechanical (QM/MM) study of N 1s X-ray photoelectron (XPS) and absorption (XAS) spectra of three isonicotinamide (IN)-based organic crystals with full (1), half (2), and no (3) protonations. A complete picture of the structure–spectroscopy relation in different crystal environments was provided, and assignments to three unprotonated (pyridinic, p; amide, a 1 and a 2) sites and one protonated (pyridinic, h) N site were clearly made. We found that including distant residues as natural population analysis (NPA) point charges can effectively enhance the SCF convergence of the core states. The size of the QM part was tuned, and with some 140–170 atoms we achieved spectral convergence that can represent the infinite crystal. At the crystal structures, simulated relative binding energies deviate ≤0.3 eV to experiments. Simulated XAS spectra agree well with experiments, and with molecular orbital analysis we interpreted the π* structures as hybrid local excitation and charge transfer states (πLE–CT *) or pure LE states (πLE *). Analyses on both spectra helped understand the PT and HB nature in such organic crystals, and a debate in XPS interpretation of 3 was resolved and its XAS assignment corrected. Further, to model the dynamical effect of the proton in 2, XPS/XAS spectra were evaluated at snapshots with varying N–H distances. A continuous picture illustrates the sensitive influence of proton position to both spectra. Reduction of the N–H distance by only 0.2 Å from the crystal structure (1.1 Å) excellently reproduced both spectra. This perturbation phenomenologically models effects of vibration from the equilibrium crystal structure and environmental temperature and pressure factors.

Polynitrogen molecules and ions are important building blocks of high energy density compounds(HEDCs). High energy bonds formed at the N sites can be effectively probed by the X-ray photoelectron spectroscopy...

Truncated cluster models represent an effective way for simulating X-ray spectra of 2D materials. Here we systematically assessed the influence of two key parameters, the cluster shape (honeycomb, rectangle, or parallelogram) and size, in X-ray photoelectron (XPS) and absorption (XAS) spectra simulations of three 2D materials at five K-edges (graphene, C 1s; C3N, C/N 1s; h-BN, B/N 1s) to pursue the accuracy limit of binding energy (BE) and spectral profile predictions. Several recent XPS experiments reported BEs with differences spanning 0.3, 1.5, 0.7, 0.3, and 0.3 eV, respectively. Our calculations favor the honeycomb model for stable accuracy and fast size convergence, and a honeycomb with ~10 nm side length (120 atoms) is enough to predict accurate 1s BEs for all 2D sheets. Compared to all these experiments, predicted BEs show absolute deviations as follows: 0.4-0.7, 0.0-1.0, 0.4-1.1, 0.6-0.9, and 0.1-0.4 eV. A mean absolute deviation of 0.3 eV was achieved if we compare only to the closest experiment. We found that the sensitivity of computed BEs to different model shapes depends on systems: graphene, sensitive; C3N, weak; h-BN, very weak. This can be attributed to their more or less delocalized π electrons in this series. For this reason, a larger cluster size is required for graphene than the other two to reproduce fine structures in XAS. The general profile of XAS shows weak dependence to model shape. Our calculations provide optimal parameters and accuracy estimations that are useful for X-ray spectral simulations of general graphene-like 2D materials.